REVIEW published: 16 March 2021 doi: 10.3389/fendo.2021.648411 Pasireotide in the Personalized Treatment of Acromegaly Manel Puig-Domingo 1*, Ignacio Bernabéu 2, Antonio Picó 3, Betina Biagetti 4, Joan Gil 1, Cristina Alvarez-Escolá 5, Mireia Jordà 1, Montserrat Marques-Pamies 1, Berta Soldevila 1, Marı́a-Angeles Gálvez 6, Rosa Cámara 7, Javier Aller 8, Cristina Lamas 9 and Mónica Marazuela 10 1Endocrinology & Nutrition Service, Germans Trias Hospital and Research Institute, Badalona, Autonomous University of Barcelona, Badalona, Spain, 2 Endocrinology & Nutrition Service, Complejo Universitario de Santiago de Compostela, Santiago de Compostela, Spain, 3 Endocrinology & Nutrition Service, University Hospital, Alicante, Spain, 4 Endocrinology & Nutrition Service, Vall d’Hebron University Hospital, Barcelona, Spain, 5 Endocrinology & Nutrition Service, La Paz Hospital, Madrid, Spain, 6 Endocrinology & Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain, 7 Endocrinology & Nutrition Service, La Fe University Hospital, Valencia, Spain, 8 Endocrinology & Nutrition Service, Puerta de Hierro University Hospital, Majadahonda, Spain, 9 Endocrinology & Nutrition Service, Complejo Hospitalario Universitario de Albacete, Edited by: Albacete, Spain, 10 Endocrinology & Nutrition Service, La Princesa University Hospital, Madrid, Spain Manuel D. Gahete, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Spain The delay in controlling the disease in patients who do not respond to first-line treatment Reviewed by: with first generation somatostatin receptor ligands (first-generation SRLs) can be Mônica Gadelha, Federal University of Rio de Janeiro, quantified in years, as every modification in the medical therapy requires some months Brazil to be fully evaluated. Considering this, acromegaly treatment should benefit from Eva Christine Coopmans, Erasmus Medical Center, Netherlands personalized medicine therapeutic approach by using biomarkers identifying drug *Correspondence: response. Pasireotide has been positioned mostly as a compound to be used in first- Manel Puig-Domingo generation SRLs resistant patients and after surgical failure, but sufficient data are now mpuigd@igtp.cat available to indicate it is a first line therapy for patients with certain characteristics. Specialty section: Pasireotide has been proved to be useful in patients in which hyperintensity T2 MRI This article was submitted to signal is shown and in those depicting low SST2 and high expression of SST5, low or Pituitary Endocrinology, mutated AIP condition and sparsely granulated immunohistochemical pattern. This a section of the journal Frontiers in Endocrinology combination of clinical and pathological characteristics is unique for certain patients and Received: 31 December 2020 seems to cluster in the same cases, strongly suggesting an etiopathogenic link. Thus, in Accepted: 22 February 2021 this paper we propose to include this clinico-pathologic phenotype in the therapeutic Published: 16 March 2021 algorithm, which would allow us to use as first line medical treatment those compounds Citation: Puig-Domingo M, Bernabéu I, Picó A, with the highest potential for achieving the fastest control of GH hypersecretion as well as Biagetti B, Gil J, Alvarez-Escolá C, a positive effect upon tumor shrinkage, therefore accelerating the implementation of Jordà M, Marques-Pamies M, precision medicine for acromegaly. Moreover, we suggest the development, validation Soldevila B, Gálvez M-A, Cámara R, Aller J, Lamas C and Marazuela M and clinical use of a pasireotide acute test, able to identify patients responsive to (2021) Pasireotide in the Personalized pasireotide LAR as the acute octreotide test is able to do for SRLs. Treatment of Acromegaly. Front. Endocrinol. 12:648411. Keywords: resistance to medical treatment in acromegaly, somatostatin analogues, somatostatin receptor ligands, doi: 10.3389/fendo.2021.648411 personalized medicine, somatotroph adenoma, growth hormone, PitNETs, endocrine tumors Frontiers in Endocrinology | www.frontiersin.org 1 March 2021 | Volume 12 | Article 648411 Puig-Domingo et al. Personalized Treatment of Acromegaly With Pasireotide INTRODUCTION generation somatostatin receptor ligands (first-generation SRLs), second-generation somatostatin analogs such as Acromegaly is a heterogeneous disease. Somatotropinomas, the pasireotide, the GH receptor antagonist pegvisomant, and cause of acromegaly in more than 95% of cases (1) as all others as antisense oligonucleotide drugs (18), these latter neuroendocrine tumors, show an intrinsic biologic currently in clinical development, but potentially available in heterogeneity (2). These tumors present a clinical expression the years to come. ranging from a small localized microadenoma with limited or In the mid-’70s it was discovered that dopaminergic controllable biochemical activity to large, invasive, and highly stimulation, contrary to what happens in physiological active macroadenomas sometimes poorly responsive to conditions, reduced GH secretion in acromegaly (19, 20). pharmacologic agents acting on the tumor. Thus, this Dopamine receptor D2 is the predominant dopamine receptor heterogeneity is also reflected in the therapeutic response found in these adenomas (21, 22), and until the ‘80s dopamine observed in every single case to the different medical options agonists (DA) were the only pharmacological agents for currently available. Historically, clinical guidelines have not acromegaly treatment. Cabergoline is the DA currently used included a personalized approach when recommending the due to its higher efficacy and better tolerability in comparison to best treatment option for a specific patient (3–5). Most if not bromocriptine (23, 24). It presents a very safe profile with mild all current treatment algorithms for acromegaly are based on a side-effects, is cheap, and is taken orally (25). However, its “trial and error” approach which precludes the use of added efficacy, as monotherapy for acromegaly, is relatively low treatment options when the disease is not controlled with the regarding IGF-1 levels reduction; it can be considered as first- former prescribed drug (6). In many therapeutic indications line medical therapy only for patients with modestly elevated GH -mostly in the cancer field- there has been a conscious move and IGF-1 levels (IGF-1 <2.5 x ULN). towards personalizing treatment with medication that best Somatotropinomas express somatostatin receptors (SSTs), matches the characteristics of the disease; however, this trend especially SST2 and SST5 (26). Somatostatin, as a physiological has not yet fully taken hold in the management of patients inhibitor of GH secretion, has been used for the treatment of with acromegaly. acromegaly, by developing long-acting compounds. The first- Due to the current diversity of treatments options, mostly generation short-acting somatostatin receptor ligands (SRLs) those of pharmacologic nature, it is time to include in medical octreotide and lanreotide were the first developed (27, 28). guidelines for acromegaly, recommendations based on Both show a high affinity for SST2 receptors. Thereafter, two biomarkers that could reliably identify a positive drug response long-acting formulations of both octreotide (octreotide Long- for a given patient. Acting Release-LAR) and lanreotide (lanreotide autogel-ATG) Lately, different authors have suggested to move on also in the were available, allowing monthly injections, a very convenient case of medical treatment of acromegaly and set up characteristic for the patient’s compliance. Besides reducing GH recommendations for defining algorithms allowing to and IGF-1, they also provide a substantial tumor reduction effect implement precision medicine in acromegaly patients (7–11). that makes them very interesting for acromegaly treatment (29– Regarding medical treatment of acromegaly, different 32). Additionally, a new formulation of SRLs, which is allow oral imaging (12) and functional tests performed at the time of administration of octreotide, has recently demonstrated its diagnosis, before surgical treatment (13, 14), and relevant efficacy and safety in patient optimally controlled with the information obtained from the pathological sample tumor parenteral formulation, thus facilitating treatment compliance when the patient is operated (15, 16) could be useful to include in those patients reluctant to receive monthly injections (33) as predictor biomarkers in the therapeutic algorithm, suggesting First-generation SRLs have been considered as the first-line that we are currently much closer to personalized treatment for medical acromegaly treatment (17) until now. They present a acromegaly. The implantation of a treatment algorithm based better performance in normalizing GH and IGF-1 levels than upon the prognostic and predicate value of specific biomarkers cabergoline, although roughly, only about 50% of patients identifying the response to a given drug has the potential to be normalize hormonal parameters (34, 35), and large differences more efficacious and cost-effective in the long run. in biochemical response rates of first-generation SRLs have been reported (ranging between 25% - 70%). This is probably due in part to different definitions of what is considered as a good biochemical response (36), but certainly also a consequence of CURRENT OPTIONS OF the intrinsic heterogeneity of somatotropinomas regarding SSTs PHARMACOLOGIC TREATMENT OF expression and other target molecules deployed by these tumors ACROMEGALY which influence medical therapeutic response. The criteria to define a full response to first-generation SRLs are generally The general aim of therapy in acromegaly is to suppress similar across all studies, although with some variations in GH hypersecretion of GH and IGF-1, consequently eliminating threshold levels. Ideally, both, IGF-1 and GH levels, should be morbidity and reducing mortality rates (17). When considered for achieving a complete therapeutic response. On pharmacologic treatment is to be used, there are currently the other hand, some authors combine the biochemical targets different compounds including dopamine agonists, first- with the antitumoral effects in the definition of response to first- Frontiers in Endocrinology | www.frontiersin.org 2 March 2021 | Volume 12 | Article 648411 Puig-Domingo et al. Personalized Treatment of Acromegaly With Pasireotide generation SRLs, but the majority of articles lack a clear cut-off decreases IGF-1 levels in serum and raises GH levels due to the when using these criteria (35, 37). hypothalamic feedback loop (49). Therefore, the only Moreover, some authors have defined the concept of partial biochemical marker of pegvisomant performance is IGF-1. response to SRLs. This latter condition tries to reflect a clinical Pasireotide and pasireotide-LAR were developed as a reality that has led to the implementation of the use of SRLs in multireceptor-targeted SRL with a superior efficacy over combination with other drugs if first-generation SRLs’ effect is octreotide-LAR and it has been considered so far as a second- somehow clinically significant but doesn’t fully normalize GH generation SRLs (50, 51). It could be mostly beneficial in young and IGF-1 levels. patients who show tumor growth while receiving medical One of the most used classifications is the one proposed by therapy, in patients with a headache not responsive or Colao et al. (36), which defines the full response to SRLs as intolerant to the other medical treatments and one of the most control of GH and IGF-1 levels together with >20% tumor important group for monotherapy with pasireotide are patients shrinkage in patients treated as first-line, or control of GH and without diabetes which use low pegvisomant doses (≤80 mg/ IGF-1 levels and >20% tumor shrinkage or stabilization of tumor week) during first-generation SRL and pegvisomant combination remnant in patients treated in second-line, or no tumor on treatment. Pasireotide may be also used in combination with magnetic resonance imaging at baseline. Partial response pegvisomant if the other combination therapies do not control includes a significant decrease (>50%) of GH and/or IGF-1 biochemical targets or disease symptoms (52). levels with no achievement of normal levels and/or >20% In those patients requiring combination treatment with first- tumor shrinkage. And finally, poor response or resistance to generation SRLs and pegvisomant, switching first-generation SRLs is defined as a non-clinically significant decrease of GH and SRLs to pasireotide in the combined modality is able to reduce IGF-1 levels and no tumor shrinkage. by 66% the dose of pegvisomant (53, 54). Of particular interest To avoid the variability over time of IGF-1 measurement, are the effects of pasireotide upon tumor volume reduction; other authors use IGF-1 SD score (SDS). In this case, controlled short-acting pasireotide has shown tumor reduction >20% in disease or full response is considered when IGF-1 values are 56% of patients after 6 months of treatment (55), and when below 2 SDS -or normal by definition-, partial response if SDS is comparing this effect with the one obtained by octreotide LAR, between 2 and 3 SDS, and non-response when greater than 3 SDS the mean decrease for this latter compound is 42% volume (12). First-generation SRLs have been recommended as first-line reduction and 54% for pasireotide (56). In special etiologies of therapy in non-resectable GH-producing tumors, even if it is well acromegaly, such as in cases of AIP mutation and x-linked known that they provide biochemical control only in about 50% acrogigantism in which these patients are bearing large tumors, of cases. Therefore, identifying biomarkers of first-generation the indication of pasireotide may be more convenient (57–59). SRLs response could be very useful, and nowadays it is still a Pasireotide-LAR shows a good tolerability profile, similar to somehow unmet need. Several studies have proven that surgical SRLs. Amelioration of acromegaly symptom score have been debulking of these tumors improves SRLs response (38–40). reported to be superior with pasireotide than with first- Consequently, the current general consensus is to perform generation SRLs (51). However, hyperglycemia is a relatively surgical debulking even if the surgical cure is unlikely, both to common effect and has been perceived as one of the unfavorable alleviate mass effect and to improve SRLs treatment response. factors for its use in acromegaly and Cushing disease, especially Improvement of first-generation SRLs response after surgical in diabetic or prediabetic patients at baseline. However, debulking seems to be mostly related to the reduction in tumor achieving good glycemic control has been demonstrated size, but not all tumors show the same response to SRLs after manageable with standard anti-diabetic therapy (60, 61). surgery, even with a similar residual tumor mass. First-generation SRLs are also used as preoperative treatment for ameliorating comorbidities and reducing tumor volume to IMAGING MARKERS OF RESPONSE TO improve surgical outcomes (41). A recent meta-analysis has PASIREOTIDE demonstrated better short-term cure rates in acromegaly patients after presurgical SRLs treatment, but its impact on the The T2-weighted MRI signal has demonstrated to anticipate long-term results is unclear (42). somatotropinoma response to first-generation SRLs as well as to Pegvisomant was generated by John Kopchick and Wen Chen pasireotide (12, 62). Densely granulated (DG) somatotropinomas at Ohio University in 1987 and approved for the treatment of use to present a hypointense T2-weighted signal, while most of the acromegaly in 2003 (43, 44). This GHR antagonist was somatotropinomas depicting a sparsely granulated pattern use to be PEGylated, extending the half-life to about 70 hours. either isointense or hyperintense when compared to the cerebral Nowadays, it is used as a second-line treatment for patients cortex signal. DG pattern is linked to a favorable response to SRLs not controlled with first-generation SRLs (17). while SG is not. Moreover, the MRI signal as a predictor of response The first initial trials demonstrated over 90% of IGF-1 to first-generation SRLs is also useful after surgical failure and normalization in patients resistant to first-generation SRLs (45, should always be assessed as a response biomarker because surgery 46). Virtually all patients with acromegaly can be controlled with does not modify MRI tumor intrinsic signal. Patients showing a pegvisomant, but clinical, real-life registries showed lower IGF-1 hypointense T2-weighted signal use to present a higher percentage remission rates of about 60-70% (46–48). Pegvisomant rapidly of IGF-I decrease after 6 months of treatment with first-generation Frontiers in Endocrinology | www.frontiersin.org 3 March 2021 | Volume 12 | Article 648411 Puig-Domingo et al. Personalized Treatment of Acromegaly With Pasireotide SRLs; and conversely there is a higher percentage of patients with We formulated a short version of the AOT that was able to hyperintense signal achieving less than 50% decrease in IGF-I (63). predict quite accurately the long-term response to SRLs As MRI is always done in patient diagnosis assessment, no matter if treatment in acromegalic patients. Mostly, it serves to identify the surgical treatment will be performed or not, the inclusion of T2- non-responders to first-generation SRLs, thus allowing progress weighted signal evaluation is very recommendable as it helps to in the classic sequential therapeutic algorithm and introducing identify patient response to treatment. Finally, machine learning- the next available drugs, mostly until recently, pegvisomant or based texture analysis of T2-weighted MRI images has recently been cabergoline in those cases of almost complete response to SRLs. developed and can correctly classify response to first-generation In our experience, a GH nadir of 9.2 ng/ml predicted IGF1 <3 SD SRLs in more than 80% of the patients. Machine learning-based with 82% sensitivity and 58% specificity (75% PPV, 67% NPV), texture analysis performs better than qualitative and quantitative and a GH nadir 3.6 ng/ml predicted IGF1<2 SD with a 75% evaluation of relative T2 signal intensity and immunohistochemical sensitivity and a 58% specificity (33% PPV and 89% NPV); evaluation (64). therefore, the NPV clearly serves to distinguish between partial T2-weighted relative signal intensity (rSI) has been also non-responders and true SRLs resistant cases. This short version strongly correlated with biochemical sensitivity to SRLs. The test is cost-effective and useful in the clinical practice as with two cut-off value of T2-weighted rSI to distinguish biochemical GH measurements -basal and at 2 hours nadir after sc injection sensitivity was found in one study to be 1.205, with a positive of 100 mcg of regular somatostatin-, it is sufficient for response predictive value (PPV) of 81.5% and a negative predictive value assessment. In our initial series in which 26 consecutive patients (NPV) of 77.3% (65). Inasmuch, T2-weighted rSI correlated with were studied, we found a positive correlation between post- the expression of SST5 and quantitatively predicted the treatment IGF-I values at 12 months and GH levels during biochemical efficacy of first-generation SRLs. These findings AOT (rs 0.76; p>0.0001). The AOT may be also useful after are of much interest regarding the prediction of response to surgical debulking, as a decreased residual tumor may become pasireotide, thus further studies in this regard are warranted. responsive to SRLs in some patients (38–40) and this new T2-weighted hyperintensity signal has been recently linked to situation could be identified with a postsurgical AOT. the identification of responsiveness to pasireotide (62), since In a more recent study by Wang et at in 2016, using the long higher T2-signal intensity adenomas at baseline were correlated 6-hour version it was found that the AOT was efficient and with better hormonal response levels during 3 and 9 months of accurate for identification of SRLs response (sensitivity 93.8%, pasireotide treatment and not tumor shrinkage. But shrinkage is specificity 85.7%); AOT was also very informative regarding also frequently observed in tumors harboring hyperintense T2- tumor size decrease prediction (sensitivity 84.8%, specificity weighted MRI signal when treated with this compound, 87.5%), as well as providing definite and consistent data on the supporting the potential antitumor activity of pasireotide (66). usefulness of such procedure (14). In the light of this data, it is evident that a pasireotide acute test should be designed and its value assessed as a predictor to pasireotide LAR response in acromegaly. It may be relatively FUNCTIONAL TESTS FOR PREDICTION feasible to perform a validation study at an international level in OF PASIREOTIDE RESPONSE which this hypothesis would be proved. Performing an acute octreotide and a pasireotide test in a single patient in a 24 h Functional tests may help to identify either pathologic hormonal period would allow to know very quickly which treatment would situations as well as response to specific compounds; this may work best for a given patient, saving time to achieve also be the case for pasireotide. The acute octreotide test (AOT) hormonal control. was initially formulated in 1989 by Lamberts in order to evaluate the duration of the effect of short-acting somatostatin therapeutic formulations available in the late ‘80s and thus deciding the number of injections per day required for a given patient. Since MOLECULAR MARKERS OF RESPONSE the refinement of SRLs preparations, with long-acting TO PASIREOTIDE compounds available for more than 15 years, the AOT was virtually abandoned until this procedure was reconsidered as a As for the treatment of acromegaly for patients not cured by potentially useful tool for prediction of response to long-acting surgery, different studies have been performed so far in order to SRLs. Some studies evaluating its performance as a predictor of identify biomarkers of response to SRLs in these cases, which therapeutic response have been published, being the overall accounts for about 70% of the cases in which invasion of the results somehow conflictive, because not all the studies cavernous sinus is present. The most recent information regarding concluded that the AOT was sufficiently predictive of a good this issue indicates that E-cadherin as well as SST2 are the best or a bad response to first-generation SRL. The methodology used predictors of response to these drugs (16, 73), although other and the definition of nadir was quite heterogeneous between the molecules may be involved in the complex post-SSTs pathway studies. As a consequence, some clinicians have decided not to and this includes RAF-kinase, MAPK, PLAGL1-AIP, RET/Pit1/ use it (67–69), while others are in favor of using it (13, 14, p14ARF (74) pathways, as well as Ki-67 (75), EMT markers (76, 77) 70–72). and the presence of truncated SSTs (78). Frontiers in Endocrinology | www.frontiersin.org 4 March 2021 | Volume 12 | Article 648411 Puig-Domingo et al. Personalized Treatment of Acromegaly With Pasireotide Regarding pasireotide, due to its SSTs unique multi-ligand generation SRLs, the same may apply for prediction of response capacity, it is expected that either SST2 or SST5 quantitative to pasireotide; thus, validation studies are warranted for expression measurements may inform to what extent those this latter. tumors depicting these SSTs might be more prone to a positive GH receptor (GHR) polymorphisms, and particularly d3- therapeutic response. Pasireotide shows the highest affinity for GHR have been involved in different sensitivity to GH and to the SST5, followed by SST2, SST3, and SST1 (79), although it different necessity of pegvisomant dosage to get hormonal has a slightly lower affinity -but still important- to SST2 than control during acromegaly treatment (88). Surprisingly, d3- first-generation SRLs. In recent studies (15, 80, 81), it has GHR has been linked to resistance to pasireotide treatment in been shown that in somatotropinomas depicting a SST5 a retrospective study (81). Although no explanation is so far immunohistochemical score of 2 or 3, a positive response to available, a worse response to first-generation SRLs was pasireotide is observed in about 50% of the cases resistant to first- described in patients carrying d3-GHR genotype (89). generation SRLs; SST3 and AIP expression did not influence the Therefore, although current results are very promising, response to pasireotide, while sparsely granulated adenomas additional research in the determinants of pasireotide response responded better compared to densely granulated. However, in is required for the identification of more biomarkers able to most of the tumors of unselected patients, pasireotide seems to complement current predictive factors and to increase the exert its biological effects predominantly through SST2 (82). required accuracy for personalized treatment. Moreover, a lack or a very low SST5 expression is in any case a strong predictor of non-responsiveness to pasireotide (15). And, in fact, even a low expression of SST2 is sufficient to activate DISCUSSION a biologic response as pasireotide does not stimulate SST2 internalization, as first-generaton SRLs do, and therefore the The “trial and error” approach that has driven clinical practice of receptor remains longer in the membrane (83). Only in those acromegaly patients until now, based on the sequential addition subjects resistant to first-generation SRLs, harboring tumors with of different compounds starting always with SRLs, is no more negligible SST2 expression, pasireotide can be also effective acting sustainable in the 21st century considering the high failure rate of particularly through SST5 (80). Besides the different receptor these latter drugs. The delay in controlling the disease in patients binding affinity, pasireotide exhibits different functional who do not respond to SRLs as the first-line treatment can be properties compared to first-generation SRLs when binding to quantified in years, as every modification in the medical therapy SST5, and particularly SST2. However, in one of the recently requires some months to be fully evaluated. Thus, it has been published studies, high expression of SST5 was controversially proposed that acromegaly patients should benefit from a associated with pasireotide resistance in some cases (81). Also, therapeutic approach by using molecular analysis but also the AIP low expression tumors may be pasireotide-responsive, information provided by functional and imaging procedures (7– indicating that this pathway is not exclusively implicated in the 9, 90, 91). biological response to pasireotide, in opposition to what happens Thus, a modern treatment algorithm of acromegaly should with first-generation SRLs, in which it plays an important role; be based on the selection of patients at the time of diagnosis this has been recently described in AIP mutated acromegaly according to their T2 MRI signal and response to regular patients (84). Additionally, data from a somatotroph-specific octreotide and pasireotide acute tests, provided that the latter AIP knock-out mouse model have shown a lowering IGF-1 will be developed and validated. Those patients with a positive effect of pasireotide (85). Hence, it may be proposed that the response to the acute compound tests would be good candidates best pharmacologic treatment in acromegaly AIP mutated for any of them, and a specific choice would also consider patients should be pasireotide. clinical conditions particularities such as age and diabetes Pasireotide is able to activate phosphorylation of Threonine coexistence, as well as the presence of headache. Together 333 residue of SST5, a key specific biological target of pasireotide with this, hypointensity T2-weighted signal would support action regulating SST5 trafficking and internalization, while this the use of first-generation SRLs while hyperintensity would is not observed for first-generation SRLs (86).These differences support pasireotide. In those cases in which acute octreotide include SSTs pathway activation and modulation of receptors or pasireotide test would not achieve predictive cut-off of phosphorylation, internalization, and trafficking, involving a full response, or imaging is not concordant, the addition of number of molecules that regulate membrane receptor pegvisomant as a combination or if cut-off of the acute test functions, such as b-arrestins (87). indicates resistance to first-generation SRLs or pasireotide, Taken together, these data indicate that, in addition to monotherapy with pegvisomant would be the best option effectiveness conferred through SST2 binding (74), those (Figure 1). tumors with a specific biologic profile, namely low or absent After surgical therapy, consideration of molecular and SST2 and high SST5 in a low AIP expression sparsely granulated pathologic patterns may be very helpful in those cases not rather than densely granulated, will also be responsive to achieving curation. Therefore, when the densely granulated pasireotide and in these particular cases, it would be the best pattern and high expression of E-cadherin, SST2, low SST5, pharmacologic treatment option. However, if a higher accuracy and Ki-67 are present, first-generation SRLs would be the best is needed in single patients’ prediction when it comes to first- option, while the opposite pattern, namely, sparsely granulated Frontiers in Endocrinology | www.frontiersin.org 5 March 2021 | Volume 12 | Article 648411 Puig-Domingo et al. Personalized Treatment of Acromegaly With Pasireotide FIGURE 1 | Therapeutic algorithm for medical treatment of acromegaly before surgery. FIGURE 2 | Therapeutic algorithm for medical treatment of acromegaly after non-curable surgery. pattern, low SST2 and E-cadherin, detectable SST5, low or absent AUTHOR CONTRIBUTIONS AIP, and high Ki-67, would best fit for pasireotide (Figure 2). As pegvisomant does not act on the tumor itself, this latter MP-D, IB, MM and BB contributed to conception and design of information does not apply in the decision-making process to the review. MP-D wrote the main manuscript. All authors implement this compound, and obviously, the best clinical contributed to the article and approved the submitted version. practice judgement from an experienced team would prevail when conflicting information is present in a given patient. FUNDING The current scientific knowledge is starting to be consistent enough to change the spirit of “trial and error” therapeutic This work was partly supported by a grant from Instituto Carlos algorithm and promote a much modern one that would allow III, Madrid, Spain, on personalized treatment of acromegaly precision medicine soon. Some tools are still waiting to be (PMP:15/00027). Recordati financed medical writing for style developed, such as the acute pasireotide test, that certainly will and editing but did not influence nor had access to the content of be of much aid in the context of personalized medicine. this paper before its submission. Frontiers in Endocrinology | www.frontiersin.org 6 March 2021 | Volume 12 | Article 648411 Puig-Domingo et al. Personalized Treatment of Acromegaly With Pasireotide REFERENCES 20. Peillon F, Cesselin F, Zygelman N, Brandi A, Mauborgne A. [Effect of L dopa, dopamine and CB 154 on prolactin secretion from human pituitary adenomas 1. Melmed S. Medical progress: Acromegaly. N Engl J Med (2006) 355:2558–73. in vitro (proceedings) (author’s transl)]. Ann Endocrinol (Paris) (1978) doi: 10.1056/NEJMra062453 39:255–7. 2. Pedraza-Aré valo S, Gahete MD, Alors-Pé rez E, Luque RM, Castaño JP. 21. Bression D, Brandi AM, Nousbaum A, Le Dafniet M, Racadot J, Peillon F. 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Somatostatin receptor expression and patients’ Ipsen, and Novartis. response to targeted medical treatment in pituitary tumors: evidences and controversies. J Endocrinol Invest (2020) 43:1543–53. doi: 10.1007/s40618- The remaining authors declare that the research was conducted in the absence of 020-01335-0 any commercial or financial relationships that could be construed as a potential 81. Chiloiro S, Giampietro A, Mirra F, Donfrancesco F, Tartaglione T, Mattogno conflict of interest. PP, et al. Pegvisomant and Pasireotide LAR as second line therapy in acromegaly: Clinical effectiveness and predictors of response. Eur J Copyright © 2021 Puig-Domingo, Bernabe ́u, Picó, Biagetti, Gil, Alvarez-Escolá, Jordà, Endocrinol (2020). doi: 10.1530/EJE-20-0767 Marques-Pamies, Soldevila, Gálvez, Cámara, Aller, Lamas and Marazuela. This is an 82. 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